DESCRIPTION: Neurological disorders affect 20% of Americans, with an estimated annual cost of $400 billion. Current clinical approaches are unable to effectively restore the functions in damaged nerves. Our long-term goal is to use neuro-inductive biomaterials to restore functions in damaged nervous tissues. The objective of this proposal is to elucidate the structure-function relationship of a unique family of neurotransmitter-based biomaterials and explore their potential to regenerate peripheral nerves. The central hypothesis is that rationally-designed biodegradable materials with neurotransmitter functional groups can induce precise responses from neurons through their specific neurotransmitter receptors, and enhance their survival and regenerative capability. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: (1) Control neuron-material interactions by systematically varying the structure of neurotransmitter-based polymers; and (2) Regenerate peripheral nerves using electrospun neurotransmitter-based polymer nanofibers. Under the first aim, an already proven synthesis strategy will be used to systematically vary the structure of the polymer regarding the backbone flexibility and hydrophilicity, and the type and density of neurotransmitters. We will examine the effects of a structural perturbation on a material's interactions with neurons in vitro and nerves in vivo. Under the second aim, we will create nerve guidance conduits using electrospun nanofibers with equipment that is already in our laboratory. The efficacy of these conduits in regenerating transected sciatic nerve will be evaluated using behavioral, electrophysiological, histological, and immunohistochemical methods. This approach is innovative because it uses chemical messengers to impart bioactivity to synthetic biodegradable polymers. The combination of work in aims 1 and 2 is expected to create a biomaterial platform capable of presenting defined density of neurotransmitter functional groups and nano-scale contact guidance to control neuronal activities. This multidisciplinary proposal combines the complementary expertise of the Principal Investigator in biomaterial design and regenerative medicine, and the Collaborators in neuropathic pain and electrophysiology. When successful, the proposed research will represent a significant advance in the rational design of biomaterials, and may enable new approaches in functional nerve regeneration. Current clinical approaches are unable to effectively restore the functions in damaged nerves. The proposed research seeks to determine the structure-function relationship of a family of novel neurotransmitter-based biomaterials and to apply these materials in functional nerve regeneration. [unreadable] [unreadable] [unreadable]